Molecular recognition in the regulation of gene expression and signaling

We study the structure, molecular recognition and dynamics of biomolecules in solution using integrative structural biology approaches combining NMR-spectroscopy and Small Angle Neutron and/or X-ray Scattering (SAXS/SANS) data in solution with X-ray crystallography and cryo-EM. In this context biomolecular NMR provides unique information for characterizing the interactions and dynamics of biological macromolecules in solution. Advances in NMR methodology and instrumentation allow to characterize molecular interactions and conformational dynamics of high molecular weight multi-domain proteins and complexes, which we combine with crystallography and cryo-EM structural analysis. We use such integrated approaches combined with computational methods for structure-based drug discovery to develop novel therapeutic concepts for treating human disease.

A main focus in the Sattler group is to understand the structural basis of regulatory protein-RNA interactions that are functionally important for various aspects of gene expression, such as the regulation of (alternative) pre-mRNA splicing and gene silencing by non-coding RNAs (siRNAs, miRNAs). More than 90% of human multi-exon genes are alternatively spliced and misregulation of splicing is linked to various human diseases. Early and critical steps in the regulation of alternative splicing involve the binding of trans-acting factors to the pre-mRNA to modulate the splicing decision. These are multi-domain RNA binding proteins that mediate dynamic molecular interactions, where specific and tight complexes are formed by the cooperative combination of multiple weak protein-protein and protein-RNA interactions. Current projects focus on protein-protein and protein-RNA interactions that play important roles in the recognition of the 3' splice site by U2AF and SF1 and the role and mechanisms of alternative splicing factors, such as SPF45, TIA-1 and RBM5. We combine biochemical methods, chemical probing (SHAPE) and structural biology to study the structure and function of lncRNAs in human disease.

Another area of research is structural investigations of the molecular chaperone Hsp90 and its interactions with co-chaperones and clients and protein complexes involved in disease-linked cellular pathways, as well as molecular mechanisms of peroxisome biogenesis, which involves proteins with extended intrinsically disordered regions. Here, we focus on understanding the structural mechanisms, conformational dynamics and allosteric communication that underlie the molecular functions of these proteins.

We have established infrastructure and expertise in structure-based discovery of small molecule inhibitors as i) starting points for pharmaceutical interference and ii) as tools to modulate and monitor cellular signaling. These studies aim at identifying optimized small chemical compounds using structure-guided approaches. NMR is an efficient tool for detecting and mapping ligand binding of biomolecules, and well suited to study small molecule binding to RNA and RNA/protein complexes as drug targets.